CN114436979B - Method for synthesizing 1,2, 4-triazole-3-carboxylic acid methyl ester - Google Patents
Method for synthesizing 1,2, 4-triazole-3-carboxylic acid methyl ester Download PDFInfo
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- CN114436979B CN114436979B CN202210161658.5A CN202210161658A CN114436979B CN 114436979 B CN114436979 B CN 114436979B CN 202210161658 A CN202210161658 A CN 202210161658A CN 114436979 B CN114436979 B CN 114436979B
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- QMPFMODFBNEYJH-UHFFFAOYSA-N methyl 1h-1,2,4-triazole-5-carboxylate Chemical compound COC(=O)C1=NC=NN1 QMPFMODFBNEYJH-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 33
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 13
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 24
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims abstract description 18
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 9
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 6
- 229940126062 Compound A Drugs 0.000 claims description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000003929 acidic solution Substances 0.000 abstract description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 229940098779 methanesulfonic acid Drugs 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229960000329 ribavirin Drugs 0.000 description 5
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 5
- 238000003912 environmental pollution Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000003443 antiviral agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000010413 mother solution Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- XGPOMXSYOKFBHS-UHFFFAOYSA-M sodium;trifluoromethanesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C(F)(F)F XGPOMXSYOKFBHS-UHFFFAOYSA-M 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- ZEWJFUNFEABPGL-UHFFFAOYSA-N 1,2,4-triazole-3-carboxamide Chemical compound NC(=O)C=1N=CNN=1 ZEWJFUNFEABPGL-UHFFFAOYSA-N 0.000 description 2
- -1 5-mercapto-1, 2, 4-triazole-3-carboxylic acid methyl ester Chemical compound 0.000 description 2
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000004880 explosion Methods 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- RJPLZUSZDBKXQO-UHFFFAOYSA-N 2-aminoguanidine;formic acid Chemical compound OC=O.NN=C(N)N RJPLZUSZDBKXQO-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 208000002979 Influenza in Birds Diseases 0.000 description 1
- FPGGOFQJXNBOTC-UHFFFAOYSA-N OS(O)=O.OP(O)(O)=O Chemical compound OS(O)=O.OP(O)(O)=O FPGGOFQJXNBOTC-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- TUVYSBJZBYRDHP-UHFFFAOYSA-N acetic acid;methoxymethane Chemical compound COC.CC(O)=O TUVYSBJZBYRDHP-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 206010064097 avian influenza Diseases 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- MYFXBBAEXORJNB-UHFFFAOYSA-N calcium cyanamide Chemical compound [Ca+2].[N-]=C=[N-] MYFXBBAEXORJNB-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006477 desulfuration reaction Methods 0.000 description 1
- 230000023556 desulfurization Effects 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- RPMSDLSGADVUTH-UHFFFAOYSA-N methyl 3-cyano-1,2,4-triazole-3-carboxylate Chemical compound COC(=O)C1(N=CN=N1)C#N RPMSDLSGADVUTH-UHFFFAOYSA-N 0.000 description 1
- PBTHJVDBCFJQGG-UHFFFAOYSA-N methyl azide Chemical compound CN=[N+]=[N-] PBTHJVDBCFJQGG-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 235000012773 waffles Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing 1,2, 4-triazole-3-carboxylic acid methyl ester, which comprises the following steps: in an acidic solution, the compound E is used as a raw material to react with sodium nitrite to prepare the 1,2, 4-triazole-3-carboxylic acid methyl ester.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a method for synthesizing 1,2, 4-triazole-3-carboxylic acid methyl ester.
Background
In recent years, people continuously suffer from viruses such as SARS and avian influenza, so that people continuously use antibiotics, a large number of bacteria have strong drug resistance, the viruses generate gene mutation, and the health of the human body is threatened, so that a large number of antiviral drugs are needed. Through several years of research, ribavirin, an antiviral drug, has become the first choice for people. Ribavirin (Ribavirin) was first synthesized in 1970 by the international pharmaceutical company josephson waffle, a spectroscopic antiviral drug with powerful effects, belonging to one of the synthetic nucleoside drugs, which can exert a certain inhibitory effect on a variety of DNA and RNA viruses.
Methyl 1,2, 4-triazole-3-carboxylate and 1,2, 4-triazole-3-carboxamide are important intermediates for the synthesis of ribavirin. At present, along with the wide clinical application, the ribavirin has huge yield, the demand for the 1,2, 4-triazole-3-carboxylic acid methyl ester is very high, and the market prospect of the 1,2, 4-triazole-3-carboxylic acid methyl ester is very broad. In addition, many derivatives containing reactive groups can be prepared from methyl 1,2, 4-triazole-3-carboxylate, methyl 3-cyano-1, 2, 4-triazole-3-carboxylate, 1,2, 4-triazole-3-carboxamide, and the like.
The existing reporting technologies basically have the problems of complicated route, high operation difficulty, dangerous technology, more three wastes, high cost and the like.
The method comprises the steps of (1) preparing methyl 1,2, 4-triazole-3-formate by using diethyl oxalate as a raw material, performing ammonolysis, hydrazinolysis of methyl ether acetate, and cyclization and methyl esterification, wherein the paths are as follows:
the method has the advantages of high raw material cost, low yield and more byproducts, and is not suitable for industrial production.
The method comprises the steps of (1) preparing methyl oxalate hydrazide by reacting dimethyl oxalate with hydrazine hydrate, then carrying out cyclization with ammonium thiocyanate to prepare 5-mercapto-1, 2, 4-triazole-3-carboxylic acid methyl ester, and finally carrying out oxidative desulfurization by using 30% hydrogen peroxide to obtain the target product 1,2, 4-triazole-3-carboxylic acid methyl ester. The path is as follows:
the method finally adopts 30% hydrogen peroxide with strong oxidability to desulfurate, oxygen can be generated during decomposition, explosion can be caused after the hydrogen peroxide contacts inflammable substances and organic substances, and the danger of combustion explosion is high during impact, friction and vibration, so that the process danger is high.
At present, the industrial production generally takes lime nitrogen as a raw material, aminoguanidine formic acid, trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid hydrogen salt are prepared after hydrazine hydrate hydrolysis, oxalylation is carried out, cyclization is carried out under alkaline conditions, methyl esterification is carried out, and diazotization deamination is carried out to obtain the product. The path is as follows:
the method has the advantages of complicated process, high content of three wastes and large environmental pollution, and is not suitable for process production.
As mentioned above, the synthesis process of 1,2, 4-triazole-3-carboxylic acid methyl ester reported at present has some technical problems and environmental pollution problems. The current market has large demand for 1,2, 4-triazole-3-carboxylic acid methyl ester, and a synthetic route which is simple, convenient and safe in process, low in raw material cost and environment-friendly is urgently needed.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: the invention provides a method for synthesizing 1,2, 4-triazole-3-carboxylic acid methyl ester, which solves the problems that the existing 1,2, 4-triazole-3-carboxylic acid methyl ester has complicated synthetic route, high cost and large pollution.
The invention is realized by the following technical scheme:
a method for synthesizing methyl 1,2, 4-triazole-3-carboxylate, comprising the following steps:
in a mixed acid solution, a compound E is used as a raw material to react with sodium nitrite to prepare 1,2, 4-triazole-3-carboxylic acid methyl ester; the reaction formula is as follows:
in an acidic solution, the invention promotes the amino group of the compound E to be decomposed by adding sodium nitrite to generate 1,2, 4-triazole-3-carboxylic acid methyl ester. The market price of the mixed acid solution and sodium nitrite in the reaction is low and easy to obtain, and the by-product of the reaction is ammonium salt, so that the environmental pollution is reduced to a great extent.
Further preferably, the mixed acidic solution includes any two or more of formic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, nitrous acid, hypochlorous acid, phosphoric acid, sulfurous acid, acetic acid, and acetic anhydride.
Further preferably, the mass ratio of the compound E to the sodium nitrite is 1:1-10.
Further preferably, the ratio of the compound E to the mixed acid solution is 1:1-20.
Further preferably, the reaction temperature is room temperature and the reaction time is 5 to 24 hours.
Further preferably, the compound E is prepared by the following method:
the compound C is prepared by reacting with ammonia in a solvent, the reaction temperature is 100-140 ℃, and the reaction formula is shown as follows:
further preferably, the compound C is prepared by the following method:
the compound B and trimethyl orthoformate are prepared by reaction in a solvent, the reaction temperature is 50-90 ℃, and the reaction formula is shown as follows:
further preferably, the compound B is prepared by the following method:
the compound A and methylamine are prepared by reaction in a solvent, wherein the reaction temperature is room temperature, and the reaction formula is shown as follows:
further preferably, the solvent is one or two of methanol, ethanol, n-propanol and n-butanol.
The invention has the following advantages and beneficial effects:
the synthesis process of the 1,2, 4-triazole-3-carboxylic acid methyl ester reported at present has some process problems and environmental pollution problems. The current market has large demand for 1,2, 4-triazole-3-carboxylic acid methyl ester, and a synthetic route which is simple, convenient and safe in process, low in raw material cost and environment-friendly is urgently needed. The synthesis method of the 1,2, 4-triazole-3-carboxylic acid methyl ester provided by the invention is beneficial to simplifying the route, reducing the cost and pollution, and can effectively overcome the defects existing in the prior art.
Detailed Description
The present invention will be described in further detail with reference to the following examples, for the purpose of making the objects, technical solutions and advantages of the present invention more apparent, and the description thereof is merely illustrative of the present invention and not intended to be limiting.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to one of ordinary skill in the art that: no such specific details are necessary to practice the invention. In other instances, well-known materials or methods have not been described in detail in order to avoid obscuring the present invention.
Throughout the specification, references to "one embodiment," "an embodiment," "one example," or "an example" mean: a particular feature, structure, or characteristic described in connection with the embodiment or example is included within at least one embodiment of the invention. Thus, the appearances of the phrases "in one embodiment," "in an example," or "in an example" in various places throughout this specification are not necessarily all referring to the same embodiment or example. Furthermore, the particular features, structures, or characteristics may be combined in any suitable combination and/or sub-combination in one or more embodiments or examples. Furthermore, it will be understood by those of ordinary skill in the art that the term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
The embodiment provides a method for synthesizing 1,2, 4-triazole-3-carboxylic acid methyl ester, wherein the reaction formula is as follows:
wherein: r is R 1 Is CH 3 Or CH (CH) 3 CH 2 ;R 2 Is CH 3 Or CH (CH) 3 CH 2 。
The specific synthesis steps are as follows:
step 1: the compound A and methylamine react in an organic solvent to synthesize a compound B, wherein the reaction temperature is room temperature;
step 2: the compound B and the orthoformate react in an organic solvent to synthesize a compound C, wherein the reaction temperature is 70 ℃;
step 3: the compound C and ammonia react in an organic solvent to synthesize a compound D, the compound D is continuously reacted to synthesize a compound E without treatment, and the reaction temperature is 120 ℃;
step 4: compound E and sodium nitrite are synthesized into compound F in an organic solvent, namely, the final product, namely, 1,2, 4-triazole-3-carboxylic acid methyl ester; the mass ratio of the compound E to the sodium nitrite is 1:1-5, and the ratio of the compound E to the acid solution is 1:1-15. The reaction time is 5h-24h.
In the step 1-step 3, the solvent is preferably one or two mixed alcohol solutions of methanol, ethanol, n-propanol and n-butanol; in the step 4, the organic solvent is selected from mixed acidic solution, preferably a mixed solution composed of any two or more of formic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, nitrous acid, hypochlorous acid, sulfurous acid phosphate, acetic acid and acetic anhydride.
The specific steps for the synthesis of compounds B to E are as follows:
preparation of compound B:
after 20g of methyl monoazide and 40mL of methanol were added to a 250mL single-necked flask, stirring was started, and then 56.15 g of a 9.35% methanolic methylamine solution was weighed and slowly dropped into the reaction system by using a 100mL constant pressure dropping funnel to react at room temperature for 2 hours. The reaction mixture was filtered and the filter cake was air-dried at 45℃to give 18.93g of Compound B in 95.17% yield.
Preparation of compound C:
to a 500mL single flask, 11.71g of Compound B, 150mL of methanol and 21.22g of trimethyl orthoformate were added, and the mixture was refluxed at 70℃for 15 hours. The system was filtered at reduced temperature and the filter cake was air-dried to give 13.74g of compound C in 86.33% yield.
Preparation of compound D, E:
to a 500mL jar was added 10.00g of compound C, 50mL of methanol and 12.00g of methanolic ammonia solution, and the mixture was reacted at 120℃for 5 hours. The system was cooled down, the reaction solution was filtered, and the obtained solid was air-dried at 50℃to give 7.40g of Compound E in 93.08% yield.
Example 1
The embodiment provides a preparation method of 1,2, 4-triazole-3-carboxylic acid methyl ester, which is specifically shown as follows:
to a 100mL three-necked flask, 12.6g of Compound E, 17mL of acetic acid, 34mL of acetic anhydride and 30.8g of sodium nitrite solid were added, and the mixture was reacted at room temperature for 15 hours. Adding 35mL of ice water, adding 50X3mL of DCM, extracting for three times, finally combining organic phases, washing 2 times by 25X2mL of 5% formic acid, trifluoroacetic acid, methanesulfonic acid and sodium trifluoromethanesulfonate aqueous solution, concentrating the obtained organic phase at 60 ℃ in vacuum until slightly solid appears, stopping concentrating, stirring and crystallizing the concentrated mother solution at 10 ℃ for 1h, filtering, and washing filter cakes by 10mL of DCM in sequence; and then the crude product is dried by blowing at 50 ℃ to finally obtain 8.3g of 1,2, 4-triazole-3-carboxylic acid methyl ester with the yield of 65 percent.
Example 2
The embodiment provides a preparation method of 1,2, 4-triazole-3-carboxylic acid methyl ester, which is specifically shown as follows:
to 100mL was added 12.6g of Compound E, 17mL of acetic acid, 34mL, and 46.2g of sodium nitrite solid, and the mixture was reacted at room temperature for 10 hours. Adding 35mL of ice water, adding 50X3mL of DCM, extracting for three times, finally combining organic phases, washing 2 times by 25X2mL of 5% formic acid, trifluoroacetic acid, methanesulfonic acid and sodium trifluoromethanesulfonate aqueous solution, concentrating the obtained organic phase at 60 ℃ in vacuum until slightly solid appears, stopping concentrating, stirring and crystallizing the concentrated mother solution at 10 ℃ for 1h, filtering, and washing filter cakes by 10mL of DCM in sequence; the crude product was then air-dried at 50℃to give 6.5g of methyl 1,2, 4-triazole-3-carboxylate in 51% yield.
Example 3
The embodiment provides a preparation method of 1,2, 4-triazole-3-carboxylic acid methyl ester, which is specifically shown as follows:
to 100mL was added 12.6g of Compound E, 17mL of acetic acid, 17mL, and 30.8g of sodium nitrite solid, and the mixture was reacted at room temperature for 8h. Adding 35mL of ice water, adding 50X3mL of DCM, extracting for three times, finally combining organic phases, washing 2 times by 25X2mL of 5% formic acid, trifluoroacetic acid, methanesulfonic acid and sodium trifluoromethanesulfonate aqueous solution, concentrating the obtained organic phase at 60 ℃ in vacuum until slightly solid appears, stopping concentrating, stirring and crystallizing the concentrated mother solution at 10 ℃ for 1h, filtering, and washing filter cakes by 10mL of DCM in sequence; and then the crude product is dried by blowing at 50 ℃ to finally obtain 5.7g of 1,2, 4-triazole-3-carboxylic acid methyl ester with the yield of 45 percent.
All yield calculation methods of the above examples are as follows: yield = actual yield/theoretical yield x 100%.
The foregoing description of the embodiments has been provided for the purpose of illustrating the general principles of the invention, and is not meant to limit the scope of the invention, but to limit the invention to the particular embodiments, and any modifications, equivalents, improvements, etc. that fall within the spirit and principles of the invention are intended to be included within the scope of the invention.
Claims (7)
1. A method for synthesizing methyl 1,2, 4-triazole-3-carboxylate, which is characterized by comprising the following steps:
in a mixed acid solution of acetic acid and acetic anhydride, a compound E is used as a raw material to react with sodium nitrite to prepare 1,2, 4-triazole-3-carboxylic acid methyl ester; the reaction formula is as follows:
;
the reaction temperature is room temperature, and the reaction time is 5-24 h.
2. The method for synthesizing methyl 1,2, 4-triazole-3-carboxylate according to claim 1, wherein the mass ratio of the compound E to sodium nitrite is 1:1-10.
3. The method for synthesizing methyl 1,2, 4-triazole-3-carboxylate according to claim 1, wherein the ratio of the compound E to the mixed acid solution is 1:1-20.
4. A process for the synthesis of methyl 1,2, 4-triazole-3-carboxylate according to any one of claims 1 to 3, wherein said compound E is obtained by the preparation of:
the compound C is prepared by reacting with ammonia in a solvent, the reaction temperature is 100-140 ℃, and the reaction formula is shown as follows:,R 2 is CH 3 。
5. The method for synthesizing methyl 1,2, 4-triazole-3-carboxylate according to claim 4, wherein the compound C is prepared by the following method:
the compound B and trimethyl orthoformate are prepared by reaction in a solvent, the reaction temperature is 50-90 ℃, and the reaction formula is shown as follows:
。
6. the method for synthesizing methyl 1,2, 4-triazole-3-carboxylate according to claim 5, wherein the compound B is prepared by the following method:
the compound A and methylamine are prepared by reaction in a solvent, wherein the reaction temperature is room temperature, and the reaction formula is shown as follows:
,R 1 is CH 3 Or CH (CH) 3 CH 2 。
7. The method for synthesizing methyl 1,2, 4-triazole-3-carboxylate as defined in claim 6, wherein the solvent is one or two of methanol, ethanol, n-propanol and n-butanol.
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